EA022094B1 - Crystal of amide compound - Google Patents

Abstract

Disclosed is a crystal of 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholine-4-ylcarbonyl)piperidine-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride that has excellent rennin inhibitory activity and that is useful as a prophylactic or therapeutic agent for hypertension and various organ disorders caused by hypertension, and the like. The crystal of 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholine-4-ylcarbonyl)piperidine-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride has a powder X-ray diffraction pattern showing characteristic peaks at interplanar spacings (d) of around 26.43±0.2, 7.62±0.2 and 4.32±0.2 angstroms.

Description

The present invention relates to a crystalline form of an amide compound that has excellent renning inhibitory activity and is useful as a prophylactic or therapeutic agent for hypertension or organ disorders caused by hypertension and the like.

BACKGROUND OF THE INVENTION

Patent Document 1 (νθ 2009/154300) describes 1- (4-methoxybutyl) -Y- (2methylpropyl) -Y - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl hydrochloride ] -1H-benzimidazole-2-carboxamide, which has an inhibitory effect on rennin and is applicable as a prophylactic or therapeutic agent for hypertension or organ disorders caused by hypertension and similar disorders.

List of documents

Patent Document 1: νθ 2009/154300.

SUMMARY OF THE INVENTION

Problems Solved by the Invention

There is a need for a prophylactic or therapeutic agent against hypertension or organ disorders caused by hypertension, which is excellent in efficacy and safety. The present invention aims at a new crystalline form of 1- (4methoxybutyl) -H- (2-methylpropyl) -M - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H- hydrochloride benzimidazole-2-carboxamide, which is applicable as a prophylactic or therapeutic agent for hypertension or organ disorders caused by hypertension.

Ways to solve problems

The authors of the present invention conducted extensive research and obtained hydrochloride 1- (4-methoxybutyl) -M- (2-methylpropyl) -H - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl ] 1H-benzimidazole-2-carboxamide in the form of a stable crystalline form having low hygroscopicity and a high melting point. The authors found that the crystalline form is quite satisfactory as a drug and carried out the present invention based on such results.

Accordingly, the present invention relates to (1) a crystalline form of 1- (4-methoxybutyl) -M- (2-methylpropyl) -H - [(3§, 5K) -5 (morpholin-4-ylcarbonyl) piperidin-3- hydrochloride silt] -1H-benzimidazole-2-carboxamide having a powder X-ray diffraction pattern showing characteristic peaks at interplanar spacing (s) of about 26.43 + 0.2, 7.62 ± 0.2 and 4.32 ± 0.2 angstroms ( hereinafter, sometimes abbreviated as crystalline form of the present invention), (2) a crystalline form of the above (1) having a powder x-ray showing characteristic peaks at interplanar spacing (s) of about 26.43 ± 0.2, 7.62 ± 0.2, 4.32 ± 0.2, 3.08 ± 0.2, 2.59 ± 0.2 and 2 , 33 ± 0.2 angstroms (hereinafter, sometimes abbreviated as crystalline form of type B), (3) a renin inhibiting drug containing the crystalline form according to the above (1) or (2), (4) prophylactic drug or treating a circulatory disorder containing a crystalline form according to the above (1) or (2), (5) drug for the prevention or treatment of hypertension / or organ disorders caused by hypertension, containing a crystalline form according to the above (1) or (2), (6) drug for the prevention or treatment of kidney disease, containing a crystalline form according to the above (1) or (2), (7) method prophylaxis or treatment of a disease with circulatory disorder in a mammal, comprising administering to said mammal an effective amount of a crystalline form according to the above (1) or (2), (8) method for the prevention or treatment of hypertension and / or p in a mammal disorders of organs caused by hypertension, comprising administering to said mammal an effective amount of a crystalline form according to the above (1) or (2), (9) a method for preventing or treating a mammal with kidney disease, comprising administering to said mammal an effective amount of a crystalline form according to (1) or (2), (10) the use of the crystalline form according to the above (1) or (2) for the production of a prophylactic or therapeutic agent against a disease with circulatory disorders, (11) changing the crystalline form according to the above (1) or (2) to obtain a prophylactic or therapeutic agent against hypertension and / or organ disorders caused by hypertension, (12) using the crystalline form according to the above (1) or (2) to obtain a prof a lactic or therapeutic agent for kidney disease, (13) the use of a crystalline form according to the above (1) or (2) in the prevention or treatment of a disease with circulatory disorders, (14) the use of a crystalline form according to the above (1) and and (2) the prophylaxis or treatment of hypertension and / or disorders of organs caused by hypertension, (15) use of a crystalline form of the above (1) or (2) in the prevention or treatment of kidney disease and similar diseases.

Action of the invention

The crystalline form of the present invention (for example, the above crystalline form of type B) is applicable as a pharmaceutical product, as it has excellent renning inhibitory effect, antihypertensive effect and / or protective for organs action against organ disorders caused by hypertension, etc., and low toxicity.

Brief Description of the Drawings

FIG. 1 shows a powder X-ray diffraction pattern of a crystalline form of type B (type B crystal) of Example 6.

FIG. 2 shows an X-ray powder diffraction pattern of a crystalline form of type A (crystal of type B) of Reference Example 3.

DETAILED DESCRIPTION OF THE INVENTION

The crystalline form of the present invention may be a crystalline hydrate, an unhydrated crystal, a crystalline solvate other than a hydrate, or an unsolvated crystalline form of 1- (4-methoxybutyl) -H- (2-methylpropyl) -M - [(3§, 5K) - 5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole-2-carboxamide (hereinafter sometimes referred to abbreviated as amide compound).

Examples of the hydrate include 0.5-hydrate - 5-hydrate. Of these, 0.5-hydrate, 1.0 hydrate, 1.5-hydrate, 2.0-hydrate and 2.5-hydrate are preferred. Particularly preferred are 0.5-hydrate, 1.0 hydrate and 1.5-hydrate.

The crystalline form of the present invention may be in deuterated form.

The crystalline form of the present invention can be labeled with an isotope (for example, ³ N, ¹⁴ C, ³⁵ δ, ¹²⁵ 1, etc.).

Examples of the solvated crystalline form of the amide compound include solvates with alcohols, such as a crystalline solvate with methanol, a crystalline solvate with ethanol, and the like. (preferably a crystalline solvate with C _1-6 alcohol), organic solvate crystalline hydrates impregnated with water and an organic solvent (for example, solvates of crystalline hydrates with alcohols, such as crystalline hydrates with methanol, crystalline hydrates with ethanol, etc., preferably solvates of crystalline hydrates with C alcohol _1-6 ), etc.

The crystalline form of the present invention can be obtained by transferring to the crystalline state of an amorphous amide or from another crystalline form of an amide compound.

The transition to a crystalline state is a phenomenon in which the structure of a substance changes when the temperature or pressure exceeds a certain level.

Examples of the crystalline transition method include methods known per se, for example, crystallization from solution (e.g., concentration method, gradual cooling method, reaction method (diffusion method, electrolysis method), hydrothermal growth method, flux method), vapor crystallization (e.g. gasification method (sealed tube method, gas flow method), gas phase reaction method, chemical transfer method), melt crystallization (e.g. conventional solidification method (drawing method , temperature gradient method, Bridgman method), zone melting method (concentration equalization method, floating zone method), special growing method (method in the UB8 system, liquid phase epitaxy method), fog flow method (in which the crystal is dissolved in a solvent and after filtering the solvent evaporated under atmospheric conditions), the suspension method (in which the crystal is added to the solvent in such a way that an excess of solids forms the suspension, the suspension is stirred at room temperature e, either by heating or by cooling, and the solid is collected by filtration) and a method such as drying under reduced pressure, grinding, atomization, pressure increase, and the like methods.

In order to obtain the crystalline form of the present invention, from the above methods, a suspension method is particularly preferred. In particular, a process is preferred with the addition of crystals of the amide compound to the solvent such that an excess of solid remains to form a suspension, stir the suspension and collect the solid by filtration. Solvents used include, for example, aromatic hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), saturated hydrocarbons (e.g., hexane, heptane, cyclohexane, etc.). etc.), ethers (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (e.g. acetonitrile, etc.), ketones (e.g. acetone, etc.), sulfoxides (e.g. dimethyl sulfoxide and

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etc.), acid amides (e.g. Ν, Ν-dimethylformamide, etc.), esters (e.g. ethyl acetate, etc.), alcohols (e.g. methanol, ethanol, 2-propanol, etc. e.), water and similar solvents. Such solvents can be used individually or in a mixture of two or more kinds at an appropriate ratio (for example, 1: 1-1: 100). Alcohols (e.g., 2-propanol, etc.), ketones (methyl ethyl ketone, etc.) and esters (e.g. ethyl acetate, etc.) are preferred, and ketones (methyl ethyl ketone, etc.) are more preferred. .).

The amount of solvent used is usually about 5-65 ml, preferably about 5-25 ml, relative to the amide crystals (1 g) of the amide compound.

The suspension is stirred at room temperature or at about 30-60 ° C, more preferably at about 30-60 ° C. In the present description, room temperature means about 15-30 ° C. The mixing time at about 30-60 ° C. is typically from about 30 minutes to 4 hours, preferably about 2-4 hours. The cooling temperature corresponds to room temperature. The mixing time upon cooling is typically from about 30 minutes to about 24 hours, preferably from about 30 minutes to 2 hours. The crystal of the suspension can be recovered by a known method, such as filtration and the like. The filtration temperature corresponds to room temperature, preferably about 20-30 ° C.

Alternatively, you can use the method of mixing the suspension at about 0-10 ° C. Followed by collecting crystals by filtration at about 0-10 ° C.

The crystalline form of the present invention can be obtained by drying the crystals in a known manner. Drying can be done under reduced pressure or by ventilation. The drying temperature preferably does not exceed about 60 ° C, more preferably about 4555 ° C.

Crystals other than the crystalline form of the present invention can be obtained, for example, by the method described in AO 2009/154300, or by a method similar to it. The crystalline form of the amide compound described in AO 2009/154300 is called the crystalline form of type A.

To analyze the obtained crystalline form, an X-ray crystallographic analysis method is usually used. In addition, the orientation of the crystals can also be determined by the mechanical method, by the optical method (for example, by the Raman scattering spectrum, solid state NMR, etc.) and similar methods.

The peak of the spectrum obtained by the above analysis method, by its nature, inevitably contains some measurement error. A peak-shaped crystalline form with an error range is also included in the crystalline form of the present invention. For example, ± 0.2 in the interplanar spacing (s) of an X-ray diffraction pattern means that the error is valid.

Examples of the crystalline form of 1- (4-methoxybutyl) ^ - (2-methylpropyl) ^ hydrochloride ^ [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole-2-carboxamide in the present invention include a crystalline form having a powder X-ray diffraction pattern showing characteristic peaks at interplanar spacings (s) of 26.43 ± 0.2, 7.62 ± 0.2 and 4.32 ± 0.2 angstroms, preferably a crystalline form having X-ray powder diffraction pattern showing characteristic peaks at interplanar spacing (s) 26.43 ± 0.2, 7.62 ± 0.2, 4.32 + 0.2, 3.08 ± 0.2, 2.59 ± 0, 2 and 2.33 ± 0.2 angstroms (Cree the metallic form type B).

Thus, the crystalline form of the present invention is applicable as a pharmaceutical product, since it has an exceptional renning inhibitory effect, antihypertensive effect and the like, as well as low toxicity. Moreover, since the crystalline form of the present invention shows reduced hygroscopicity and excellent stability, it can be easily worked with and can be processed into a solid pharmaceutical composition with good reproducibility.

The crystalline form of the present invention is useful as a medicament for suppressing the rennin-angiotensin system (KA system), as it acts as an inhibitor of rennin in mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, pig , monkeys, humans, etc.), inhibiting the biosynthesis of angiotensin II (ΑΙΙ), and can be used as a safe prophylactic or therapeutic agent for various diseases caused by the CA system.

Similarly, the above crystalline form of type A, 1- (4methoxybutyl) methanesulfonate - ^ (2-methylpropyl) - ^ [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole -2-carboxamide (hereinafter referred to as compound X) and 1- (4-methoxybutyl) - ^ (2-methylpropyl) - ^ [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidine- 3-yl] -1H-benzimidazole-2 carboxamide (hereinafter referred to as compound Υ) can also be used as a safe prophylactic or therapeutic agent for various diseases caused by Istemi spacecraft.

Examples of various diseases caused by the CA system include hypertension (for example, essential hypertension, renovascular hypertension, renal parenchymal hypertension, primary aldosteronism, Cushing's syndrome, etc.), circadian blood pressure abnormality, heart disease (for example, cardiac hypertrophy, acute heart failure, chronic heart failure, including congestive diastolic heart failure, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, achicardia, myocardial infarction, etc.), cerebrovascular accident (e.g. asymptomatic cerebrovascular accident, transient ischemic cerebrovascular accident, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction, etc.), cerebral edema, cerebrovascular disorder relapse and consequences of a cerebrovascular accident (e.g., neural symptoms, mental symptoms, subjective symptoms, activities of daily natural deterioration, etc.), ischemic peripheral circulation, myocardial ischemia, venous insufficiency, the development of heart failure after myocardial infarction, kidney disease (e.g. nephritis, glomerulonephritis, glomerulosclerosis, renal failure, nephrotic syndrome, thrombotic microangiopathy, dialysis complications, organ dysfunction, organ disorders, exposure to radiation, etc.), arteriosclerosis, including atherosclerosis (e.g., aneurysm, coronary sclerosis, cerebral arterial sclerosis, peripheral a arterial sclerosis, etc.), vascular hypertrophy, vascular hypertrophy or occlusion and organ disorders after the intervention (for example, percutaneous intraluminal coronary angioplasty, stent placement, coronary angioscopy, intravascular ultrasound diagnostics, intracoronary thrombolytic therapy, etc.), reocclusion and restenosis of blood vessels after bypass surgery, polycythemia, hypertension, organ disorders and vascular hypertrophy after transplantation, rejection after transplantation, ocular e diseases (e.g., glaucoma, ocular hypertension, etc.), thrombosis, multiple organ failure, endothelial dysfunction, tinnitus due to hypertension, other diseases of the circulatory system (e.g., deep vein thrombosis, occlusive peripheral circulation disorder, obliterating arteriosclerosis, thromboangiitis obliterans, ischemic cerebrovascular accident, Raynaud's disease, Buerger's disease, etc.), metabolic and nutritional disorders (e.g. diabetes, impaired glucose tolerance, insulin persistence, hyperinsulinemia, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, obesity, hyperlipidemia, hypercholesterolemia, hyperuricemia, hyperkalemia, hypernatremia, etc.) metabolic syndrome, non-alcoholic non-alcoholic steatohepatitis (non-alcoholic, non-alcoholic liver), a neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, multiple sclerosis, amyotroph lateral sclerosis, AIDS encephalopathy, etc.), disorders of the central nervous system (for example, disorders such as intracerebral hemorrhage, cerebral infarction and similar disorders, and their consequences and complications, head injury, spinal cord injury, cerebral edema, disorders sensory function, abnormality of sensory function, autonomic nervous function disorder, autonomic nervous function abnormality, etc.), dementia, migraine, memory disorders, consciousness disorders, amnesia, anxiety, symptom e.g. diseases, mental anxiety, sleep disturbance, insomnia, mental illness (e.g., depression, epilepsy, alcohol addiction, etc.), inflammatory disease (e.g., arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitis, etc. P.; inflammation after surgery; an injury; relapse of puffiness; pharyngitis; cystitis; pneumonia atopic dermatitis; inflammatory bowel disease such as Crohn’s disease, ulcerative colitis, etc .; meningitis; inflammatory eye disease; inflammatory lung diseases such as pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, etc., etc.), an allergic disease (for example, allergic rhinitis, conjunctivitis, gastrointestinal allergy, hay fever, anaphylaxis, etc. .), chronic obstructive pulmonary disease, interstitial pneumonia, keel pneumonia, collagen disease (eg systemic lupus erythematosus, scleroderma, polyarthritis, etc.), liver disease (eg, hepatitis, including chronic stage, cirrhosis, etc. ), portal hypertension, diseases digestive tract (e.g. gastritis, gastric ulcer, gastric cancer, postgastroectomy disorders, dyspepsia, esophageal ulcer, pancreatitis, colon polyp, cholelithiasis, hemorrhoids, varicose rupture of the esophagus and stomach, etc.), hematopoietic organ disease (e.g. polycythemia, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple myelosis, etc.), bone disease (e.g., fracture, refracture, osteoporosis, osteomalacia, Paget's disease skeletal system, rigid myelitis, rheumatoid arthritis, knee osteoarthritis and destruction of articular tissue in a disease like the above, etc.), a solid tumor, a tumor (e.g., malignant melanoma, malignant lymphoma, gastrointestinal cancer (e.g., stomach, intestines and etc), cancer and cachexia associated with it, metastasis, endocrine diseases (e.g., Adisson’s disease, pheochromocytoma, etc.), diseases of the urinary organs — male genital organs (eg, inflammation of the bladder, prostatomegaly, cancer p prostate gland, sexually transmitted diseases, etc.), gynecological diseases (for example, a disorder associated with menopause, toxicosis of pregnant women, endometriosis, hepatoma, ovarian disease, breast disease, sexually transmitted diseases, etc.), illness due to an environmental factor - a manufacturing factor (e.g., a disorder due to radiation, a disorder due to UV and IR laser radiation, altitude sickness, etc.), respiratory diseases (e.g., cold syndrome, pneumonia, asthma, pulmonary hypertension, blood clot in s embolism, etc.), infections (e.g., viral infections such as those caused by cytomegalovirus, influenza virus, herpes virus, etc., rickettsial infections, bacterial infections, etc.), toxemia (e.g. sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxic shock, etc.), ENT diseases (e.g., Meniere's syndrome, tinnitus, taste disorder, dizziness, dysphagia, etc.), skin diseases (e.g., keloid , hemangioma, psoriasis, etc.), eye diseases (e.g. measures, cataract, glaucoma, etc.), a systemic disease such as dialysis hypotension, myasthenia gravis, chronic fatigue syndrome, etc., and similar diseases.

Various diseases caused by the CA system also include circulatory diseases (diseases with circulatory disorders), various organ disorders caused by hypertension, and the like.

Circulatory diseases include, for example, hypertension, circadian blood pressure abnormality, heart disease, cerebrovascular disorder, cerebral edema, cerebrovascular accident, relapse and consequences of cerebrovascular accident, peripheral circulation ischemic disorder, myocardial infarction, venous insufficiency, development of heart after myocardial infarction, kidney disease, arteriosclerosis, including atherosclerosis, vascular hypertrophy or occl diarrhea and organ dysfunction after surgery, reocclusion and restenosis of blood vessels after bypass surgery, hypertension, organ disorder and vascular hypertrophy after transplantation, rejection after transplantation, thrombosis, multiple organ failure, endothelial dysfunction, tinnitus due to hypertension, migraine, hematopoietic disease dialysis hypotension and similar diseases.

Hypertensive organ disorders include heart disease, encephalopathy, kidney disease, multiple organ failure, and the like.

The crystalline form of the present invention shows low toxicity and can be safely administered orally or parenterally (e.g., by intravenous, intramuscular, subcutaneous, organ, intranasal, intradermal, instillation in the eye, intracerebral, intrectal, vaginal, intraperitoneal and intraperitoneal, and intratumoral administration near the tumor and directly into the lesion) as such or in the form of pharmaceutical compositions obtained with pharmacologically an acceptable carrier, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules) , lozenges, syrup, liquids, emulsions, suspensions, controlled release formulations (e.g., immediate release formulation, controlled release formulation, sustained release microcapsules), aerosols, films (e.g., films, sprinkle in the mouth, oral mucosal adhesive films), injections (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drops, transdermal preparation of absorption type, ointments, lotions, patches, suppositories (e.g., rectal suppository, vaginum), , beads, nasal preparations, pulmonary preparation (inhalation), eye drops, etc., according to the usual method (for example, the method described in the Japanese Pharmacopoeia, sixteenth edition, etc.).

The dose of the crystalline form in the pharmaceutical composition of the present invention is about 0.01-100 wt.% Relative to the entire composition. Varying depending on the subject of administration, route of administration, the disease being treated, etc., its dose is usually about 1-500 mg / day, preferably about 5-250 mg / day, preferably about 5-100 mg / day on the active ingredient, for example, when the substance is administered orally as a renin inhibiting agent to an adult patient (body weight 60 kg) affected by hypertension. The crystal of the present invention can be administered once a day or during the day divided into 2-3 portions.

Pharmacologically acceptable carriers that can be used to prepare the pharmaceutical composition of the present invention include various organic and inorganic carrier materials, including excipients, lubricants, binders, disintegrants, water soluble polymers for solid preparations; and solvents, solubilizers, suspending agents, isotonicity agents, buffers and sedatives for liquid preparations. If necessary, you can also use other conventional pharmaceutical additives, such as preservatives, antioxidants, colorants, sweeteners, acidifying agents, substances that promote the formation of bubbles, and flavoring agents.

Such excipients include, for example, lactose, sucrose, Ό-mannitol, starch, corn starch, microcrystalline cellulose, light silica and titanium oxide.

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Such lubricants include, for example, magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc and stearic acid.

Such binders include, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, α-starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan and low substitution hydroxypropyl cellulose.

Such disintegrants include (1) crospovidone, (2) disintegrants called superdispersants, such as croscarmellosanatrium (manufactured by PMC-Aca Cb1ea1) and carmelozalcium (produced by CoYuccn Cbc1ea1 Co. , (4) low substitution hydroxypropyl cellulose (e.g. product Ξΐιίη-Είκιι Syetka1), (5) corn starch, etc. The specified crospovidone can be any crosslinked polymer with the chemical name 1-ethanyl-2-pyrrolidinone homopolymer, including polyvinylpyrrolidone (RURP), and 1-vinyl-2-pyrrolidinone homopolymer, and examples are Collidone Cb (manufactured by BA8P), polyplas Xb (produced by 18P), polyplasdone XB-10 (produced by 18P) and polyplasdone S-10 (produced by 18P).

Such water-soluble polymers include, for example, ethanol-soluble water-soluble polymers [for example, cellulose derivatives such as hydroxypropyl cellulose (hereinafter also referred to as HPC), polyvinylpyrrolidone] and ethanol-insoluble water-soluble polymers [for example, cellulose derivatives such as hydroxypropyl hereinafter also referred to as HPMC), methyl cellulose and sodium carboxymethyl cellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum].

Such solvents include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and olive oil.

Such solubilizers include, for example, polyethylene glycol, propylene glycol, Ό-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate.

Such suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzotonium chloride and glyceryl monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.

Such tonicity agents include, for example, glucose, Ό-sorbitol, sodium chloride, glycerin and Ό-mannitol.

Such buffers include, for example, buffers of phosphates, acetates, carbonates, citrates, etc.

Such sedatives include, for example, benzyl alcohol.

Such preservatives include, for example, p-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.

Such antioxidants include, for example, sulfite, ascorbic acid and α-tocopherol.

Such colorants include, for example, food colorings such as food color yellow No. 5, food color red No. 2 and food color blue No. 2; and food kraplaki and red iron oxide.

Such sweeteners include, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and thaumatin.

Such acidifying agents include, for example, citric acid (anhydrous citric acid), tartaric acid, and malic acid.

Such bubble agents include, for example, sodium bicarbonate.

Such flavoring agents may be synthetic or naturally occurring substances and include, for example, lemon, lime, orange, menthol and strawberries.

The crystalline form of the present invention can be obtained in the form of a preparation for oral administration according to the usual method, for example, by direct compression in the presence of an excipient, disintegrant, a binder, lubricants or the like, and, if necessary, subsequent coating in the usual way in order to mask the taste, intestinal dissolution or sustained release. The enteric coating layer includes, for example, aqueous enteric polymer bases such as cellulose acetate phthalate (ATS), hydroxypropyl methyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, methacrylic acid copolymers [for example, trade name! MAE30OR (trade name; produced by VA8P), polyquid PA30 (trade name; manufactured by 8apuo Sjet1sa1)], carboxymethyl ethyl cellulose and shellac; bases for prolonged release, such as methacrylic acid copolymers [for example, Eiigadi ΝΕ30Ό (trade name), Eiigadi ΡΕ30Ό (trade name), Eiigadi K83 0Ό (trade name), etc.]; water soluble polymers; plasticizers such as triethyl citrate, polyethylene glycol, acetylated monoglycerides, triacetin and castor oil; and mixtures thereof.

The crystalline form of the present invention can be incorporated into solid preparations, such as tablets and the like, according to, for example, the method described in UO 2006/132440.

The crystalline form of the present invention, the crystalline form of type A, compound X and compound Υ can also be used in combination with other drugs. As a drug useful in combination with the crystalline form of the present invention, the crystalline form of type A, compound X and compound Υ (hereinafter referred to as the concomitant drug for short), for example, the agents listed below.

(1) Antihypertensive drugs.

An angiotensin converting enzyme inhibitor (e.g. captopril, enalapril maleate, alacepril, delapril hydrochloride, imidapril hydrochloride, quinapril hydrochloride, cilazapril, temocapril hydrochloride, trandolapril, anginaprilinoprilinoprilinoprilindril, etc.) candesartancylixetyl, candesartan, losartan, losartankali, eprosartan, valsartan, telmisartan, irbesartan, tazosartan, olmesartan, olmesartanmedoxomil, azilsartan, azilsartanmedoxomil, etc.), aldagon antagonists eronovoy receptor (spironolactone, eplerenone, etc.), calcium antagonist (e.g. verapamil hydrochloride, diltiazem hydrochloride, nifedipine, amlodipine bezylate, azelnidipine, aranidipine, efonidipine hydrochloride, nipinipinolipin dipinol hydrochloride, ninolipin dipinin felodipine, benidipine hydrochloride, manidipine hydrochloride, etc.), β-blocker (e.g. metoprolol tartrate, atenolol, propranolol hydrochloride, bisoprolol fumarate, etc.), αβ-blocker (e.g. carvedilol, etc.) , clonidine, diuretic (sodium theobromine salicylate, calcium theobromine salicylate, etiazide, cyclopentathiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethazide, benzyl hydrochlorothiazide, penflutiazide, poly-5-thiazide, methiclothiazide, azide, azide, azide, azide, azide pyrethanide, bumetanide, furosemide, etc.) and similar preparations.

(2) Antithrombotic agent.

An anticoagulant (e.g. sodium heparin, calcium heparin, calcium warfarin (warfarin), antithrombin (e.g. argatroban, dabigatran, etc.), an activated blood coagulation factor Xa inhibitor and a drug with the function of restoring the balance of the coagulating fibrinolytic system ( e.g. rivaroxaban, apixaban, edoxaban, ΥΜ-150, the compound described in νθ 02/06234, νθ 2004/048363, νθ 2005/030740, νθ 2005/058823, νθ 2005/113504 or νθ 2004/048363, etc. .), etc.), a thrombolytic drug (for example, 1PA, urokinase, tizokinase, alteplase, natepl azma, monteplase, pamiteplase), an antiplatelet drug (for example, aspirin, sulfinprazone (anturan), dipyridamole (persantin), ticlopidine hydrochloride (panaldine), cilostazol (pletal), antagonist 0P11L / 111a (e.g. Keorgo and , clopidogrel, prasugrel, ticagrelol, E5555, 8CH30348, ethyl zosapentate, beraprostatrium, saprogrelate hydrochloride, etc.) and similar preparations.

(3) A therapeutic agent for diabetes.

An insulin preparation (for example, a preparation of animal insulin extracted from the pancreas of a cow and a pig; a preparation of human insulin synthesized by genetic engineering using Exxepsoy yeast and yeast; insulin zinc; protamine zinc insulin; a fragment or derivative of insulin (e.g. ΙΝδ- 1), an oral insulin preparation, etc.), an insulin sensitizer (e.g., pioglitazone or its salt (preferably hydrochloride), rosiglitazone or its salt (preferably maleate), metaglitazene, AMO-131, balaglitazone, MV -2044, rivoglitazone, aleglitazar, higlitazar, lobeglitazone, PX-204, ΡΝ-2034, ORT-505, TNK-0921, the compound described in νθ 2007/013694, νθ 2007/018314, νθ 2008/093639 or νθ 2008/0999939 , etc.), an α-glucosidase inhibitor (e.g., voglibose, acarbose, miglitol, emiglate, etc.), biguanide (e.g. phenoformine, metformin, buformin or a salt thereof (e.g. hydrochloride, fumarate, succinate and etc.), etc.), an insulin secretion enhancing agent (e.g. sulfonylurea (e.g. tolbutamide, glibenclamide, glyclazide, chlorpropamide, tolazamide, acetohexamide, glycopyramide, glimepride, gly piside, glibuzole, etc.), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate, etc.), dipetidyl peptidase IV inhibitor (e.g., alogliptin or its salt (preferably benzoate), vildagliptin, sitagliptin, saxagliptin, ΒΙ1356 , OKS8200, MP-513, PP-00734200, PHX1149, 8K-0403, AB8-0426, TA-6666, T8021, KKR-104, 2 - [[6 - [(3K) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile or a salt thereof), β3 agonist (e.g. N-5984), OPK40 agonist (e.g. the compound described in νθ 2004/041266, νθ 2004/106276, νθ 2005/063729, νθ 2005/063725, νθ 2005/087710, νθ 2005/095338, νθ 2007/013689 il and νθ 2008/001931, etc.), an OLP-1 receptor agonist (e.g., OLP-1, ORP-1MK, liraglutide, exenatide, ΑνΕ-0010, ΒΙΜ-51077, A1b (8.35) LOB1 ( 7.37) ΝΗ ₂ , C1C-1131, albiglutide, amylin agonist (e.g. pramlintide, etc.), phosphatyrosine phosphatase inhibitors (e.g. sodium vanadate, etc.), gluconeogenesis inhibitor (e.g. inhibitor

- 7 022094 glycogen phosphorylases, glucose-6-phosphatase inhibitors, glucagon antagonists, аз-base inhibitor, etc.), §СТ2 inhibitor (sodium glucose transporter 2) (for example, depagliflozin, AUE2268. Τδ-033, Τδ-033, ΥΜδ43, 43543, -7284, remogliflozin, A8P1941, etc.), an 8CT1 inhibitor, an 11β-hydroxysteroid dehydrogenase inhibitor (e.g., BUT-3498, ΙΝΟΒ-13739, etc.), adiponectin or an agonist thereof, an inhibitor ΙΚΚ (e.g., A8- 2868, etc.), drugs that improve leptin resistance, somatostatin receptor agonists, glucokinase activators (e.g., pyragliatin, ΑΖΌ1656, ΑΖΌ 6370, TTP-355, compound described in νθ 2006/112549, νθ 2007/028135, νθ 2008/047821, νθ 2008/050821, νθ 2008/136428 or νθ 2008/156757, etc.) / ΟΙΡ (glucose-dependent insulinotropic peptide), CPK119 agonist (for example, Ρ8Ν821, etc.), PCP21, PCP analogues, and similar drugs.

(4) Therapeutic agents for diabetic complications.

Aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranerestat (A8-3201), lidorestat, etc.), a neurotrophic factor and a drug that enhances it (e.g. ΝΟΡ, ΝΤ-3, ΒΌΝΡ, neurotrophic factors and their enhancing drugs described in νθ 01/14372 (eg 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2methylphenoxy) propyl] oxazole and t etc.), a compound described in νθ 2004/039365, etc.), a PKC inhibitor (e.g. riboxystaurin mesylate, etc.), an AOE inhibitor (e.g. ABT946, phenacylthiazole bromide (ART766), EXO-226, pyridorin, pyridoxamine, etc.), an OABA receptor agonist (e.g., gabapentin, pregabalin, etc.), a serotonin-noradrenaline reuptake inhibitor (e.g., duloxetine, etc.) , a sodium channel inhibitor (e.g., lacosamide, etc.), an active oxygen scavenger (e.g., thioctic acid, etc.), a cerebral vasodilator (e.g., thiapuride, mexiletine, etc.), somatotostatin receptor agonists (e.g. , ΒΙΜ23190, etc.), an inhibitor of the signal-regulating apoptosis kinase-1 (A8K-1) and similar drugs.

(5) Antilipidemic agent.

ΗΜΟ-CoA reductase inhibitor (e.g. pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or its salt (e.g. sodium salt, calcium salt, etc.), etc.), squalene synthase inhibitors (e.g. , the compound described in νθ 97/10224, for example, Ν [[(3K, 5§) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3-dimethoxyphenyl) - 2-oxo-1,2,3,5-tetrahydro4,1-benzoxazepin-3-yl] acetyl] piperidin-4-acetic acid, etc.), fibrates (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate and etc.) anion exchange resins (e.g. colestyramine etc.), probucol, drugs based on nicotinic acid (for example, nicomol, niceritrol, niaspan, etc.), ethyl zapentate, phytosterol (for example, soy sterol, γ-oryzanol, etc.), an absorption inhibitor cholesterol (e.g. zetia, etc.), a CETP inhibitor (e.g., dalcetrapib, anacetrapib, etc.), a preparation of ω-3 fatty acid (e.g. ethyl esters of 90 ω-3 acids, etc. ) and similar drugs.

In addition to the above, they can be used in combination with other pharmaceutical ingredients, including therapeutic drugs against coronary heart disease, therapeutic drugs against chronic heart failure, therapeutic drugs against hypothyroidism, therapeutic drugs against nephrotic syndrome, therapeutic drugs against chronic renal deficiency therapeutic drugs against chronic renal anemia (e.g. erythropoietin, peginesatide, etc.), therapeutic drugs against gynecological diseases, and therapeutic drugs against infections. The drug that is used in combination may be an antibody-based drug or a nucleic acid-based drug, and the crystal of the present invention, type A crystal, compound X and compound Υ can also be used together with gene therapy.

A drug of the present invention, in which the crystalline form of the present invention and the concomitant drug are mixed or used in combination, also includes (1) a drug obtained in the form of a single pharmaceutical composition containing a crystalline form of the present invention and a concomitant drug, and (2) a drug containing a crystalline form of the present invention and a concomitant drug that are introduced into individual drugs. Hereinafter, for the sake of brevity, they are all called a joint drug of the present invention, in which a drug in which the crystalline form of type A, compound X and compound Υ and the concomitant drug are mixed or used in combination, also includes (1) a drug obtained in the form a single pharmaceutical composition containing a crystalline form of type A, compound X and compound Υ and a concomitant drug, and (2) a drug containing crystalline type A form, compound X and compound Υ and the concomitant drug, which are introduced in separate preparations. Hereinafter, for the sake of brevity, they are all called the joint remedy Ζ.

The co-agent and co-agent Ζ of the present invention can be formulated separately or simultaneously as such, or by mixing the crystalline form of the present invention and the active ingredient of the concomitant drug with a pharmaceutically acceptable carrier and the like, according to the method similar to the method for the above solid preparation of the present invention.

Although the daily dose of the co-agent of the present invention varies depending on the symptoms, race, age, gender and body weight of the subject of administration, the form administered, the type of active ingredient, and the like, it is not particularly limited until problems arise. due to side effects. For example, the daily dose of the joint oral administration agent of the present invention is typically about 0.005-100 mg, preferably about 0.05-50 mg, more preferably about 0.2-4 mg, as the total dose of the crystalline form of the present invention and concomitant drug per 1 kg of mammalian body weight, and this amount is usually administered in 1-3 servings per day.

When the co-agent of the present invention is administered, the crystalline form of the present invention can be administered after administration of the concomitant drug, or the concomitant drug can be administered after the administration of the crystalline form of the present invention, although they can be administered simultaneously. When administered at a time interval, the interval varies depending on the effective ingredient being administered, the dosage form and the route of administration, and, for example, when the concomitant drug is administered first, an example of the method when the crystalline form of the present invention is administered at a time interval is the administration at a time interval of 1 minute to 3 days, preferably 10 minutes to 1 day, more preferably 15 minutes to 1 hour after administration of the concomitant drug. When the crystalline form of the present invention is first introduced, an example of the method when the concomitant drug is administered at a time interval is administration at an interval of 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour after the crystalline administration forms of the present invention. As a method of introducing a co-agent Ζ, a similar method can be mentioned.

In the joint agent of the present invention, the content of the crystalline form of the present invention in the whole joint agent varies depending on the shape of the joint agent and, as a rule, is about 0.1-65 wt.%, Preferably 0.3-50 wt.%, More preferably 0.5-20 wt.%.

Examples

Further, the present invention is explained in detail by reference to reference examples and examples, which should not be construed as limiting.

In the following reference examples and examples, ratios given for mixed solvents are volume ratios unless otherwise indicated. Unless otherwise indicated,% shows wt.%.

The crystalline X-ray powder diffraction of type A crystalline form (hereinafter referred to as Type A crystal) is measured using a ΚΙΝΤ2000 X-ray diffractometer (Kddaki), and the crystalline X-ray powder diffraction of type B crystal (hereinafter referred to as Type B crystal) is measured using ΚΙΝΤ2500ν (Yudaki).

The content of hydrochloric acid is measured using ion chromatography (instrument ΌΙΟΝΕΧ).

The abbreviations in the reference examples and examples denote the following: c - singlet, d - doublet, t - triplet, k - quartet, dd - double doublet, dt - double triplet, m - multiplet, ear-expanded, tt triple triplet, and 1 - interaction constant.

Reference Example A. tert-Butyl- (3§, 5K) -3 - [{[1- (4-methoxybutyl) -1H-benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholine -4-ylcarbonyl) piperidine-1-carboxylate.

tert-Butyl- (3§, 5K) -3 - [{[1- (4-methoxybutyl) -1H-benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4-ylcarbonyl ) piperidine-1-carboxylate is obtained according to the method described in reference example 146 in FO 2009/154300.

tert-Butyl- (3§, 5K) -3 - [{[1- (4-methoxybutyl) -1H-benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4-ylcarbonyl ) piperidine-1-carboxylate is dissolved in toluene. The solution was heated to 35-45 ° C, heptane was added dropwise and the mixture was stirred for 30 minutes or more. The mixture was cooled to 20-30 ° C and stirred for 2 hours. The precipitated crystals were collected by filtration and washed with toluene-heptane. The crystals were dried under reduced pressure at 50 ° C. to give tert-butyl- (3§, 5K) -3 - [{[1- (4-methoxybutyl) -1H-benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5 (morpholin-4-ylcarbonyl) piperidine-1-carboxylate in the form of crystals.

Reference Example 1. 1- (4-Methoxybutyl) hydrochloride - ^ (2-methylpropyl) - ^ [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole-2 -carboxamide (type A crystal).

tert-Butyl- (3§, 5K) -3 - [{[1- (4-methoxybutyl) -1H-benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4-ylcarbonyl ) piperidine-1-carboxylate (300 g) is suspended / dissolved in 3Ν

- 9 022094 hydrochloric acid (1200 ml) and ethyl acetate (60 ml), and the mixture was stirred at 25-35 ° C for 3 hours or more. After completion of the reaction, ethyl acetate (2400 ml) was added at the same temperature. Upon completion of the addition, 25% aqueous ammonia solution (600 ml) was added while cooling. Upon completion of the addition, 5% aqueous ammonia solution (600 ml) was added to the extracted organic layer with stirring, and the mixture was stirred. After stirring, the resulting organic layer was concentrated until the solvent was completely evaporated. Upon completion of the concentration, the concentrate was dissolved in ethyl acetate (1500 ml), the solution was placed in a crystallizer, and the used container was washed with ethyl acetate (750 ml). After washing, the mixture is heated to 45-55 ° C with stirring. A 4Ν solution of hydrogen chloride in ethyl acetate (131.3 ml) was added dropwise to the heated mixture at the same temperature. Upon completion of the dropping at the same temperature, the precipitated substance is dissolved. After confirming the dissolution, heptane (750 ml) is added at 40-50 ° C and, upon completion of the addition, the mixture is cooled to 25-35 ° C. After cooling, seed crystals (300 mg) of type A crystal are added, obtained according to the method described in example 265 in GSO 2009/154300, and the mixture is stirred for 30 minutes or more. After stirring, the mixture was heated to 40-45 ° C and heptane (1500 ml) was added dropwise. Upon completion of the dropping, the mixture is stirred at the same temperature. Then the mixture was gradually cooled to 5 ° C or lower and stirred at the same temperature for 1 hour. After stirring, the crystals were collected by filtration, washed with ethyl acetate-heptane (1: 1, 600 ml) to obtain wet crystals.

The resulting wet crystals were dried under reduced pressure at 50 ° C. to give 1- (4-methoxybutyl) -P- (2-methylpropyl) -P - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidine hydrochloride -3-yl] -1Nbenzimidazole-2-carboxamide in the form of a crystalline powder (type A crystal, 198.82 g, yield 74.1%).

Reference Example 2. 1- (4-Methoxybutyl) -P- (2-methylpropyl) -L - [(3§, 5K) -5 (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole- hydrochloride 2-carboxamide (type A crystal).

1- (4-Methoxybutyl) -M- (2-methylpropyl) -L - [(3§, 5K) -5- (morpholine-4ylcarbonyl) piperidin-3-yl] -1H-benzimidazole-2-carboxamide monohydrate 1500 g) is dissolved in water (7500 ml). To the resulting solution was added the previously prepared solution of sodium bicarbonate in water (411 g NaHCO3, 7500 ml of water), and the mixture was stirred. Ethyl acetate (15000 ml) was added with stirring, and the mixture was stirred. After stirring, ethyl acetate (15000 ml) was added to the extractable aqueous layer and the mixture was stirred. After stirring, ethyl acetate (15000 ml) was added again to the extractable aqueous layer and the mixture was stirred. The resulting organic layers were combined and the mixture was concentrated to about 8 L. Ethyl acetate (10,000 ml) was added to the concentrated solution, and the mixture was concentrated to about 8 L. The concentrated solution was left to stand overnight. Ethyl acetate (10,000 ml) was added to the concentrated solution overnight, and the mixture was concentrated to about 8 L. Ethyl acetate (12500 ml) was added to the concentrated solution, and the mixture was heated to 45-55 ° C with stirring. After reaching the indicated temperature, a 4Ν solution of hydrogen chloride in ethyl acetate (730 ml) is added dropwise. After instillation, the precipitated substance dissolves. After confirming the dissolution, heptane (6000 ml) is added and the mixture is cooled to 35-40 ° C. After cooling, seed crystals (1.5 g) of type A crystal are added, obtained according to the method described in Reference Example 3, and heptane (12800 ml) is added dropwise at the same temperature. Upon completion of the dropping, the mixture is heated to 40-50 ° C and stirred for 1 h or more. After stirring, the mixture is cooled to 20-30 ° C and stirred at the same temperature for 1 h or more. After stirring, the crystals were collected by filtration and washed with ethyl acetate-heptane (1: 1, 4600 ml) to obtain wet crystals. The resulting wet crystals were dried under reduced pressure at 50 ° C. to give 1- (4-methoxybutyl) - ^ (2methylpropyl) ^ - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl hydrochloride ] -1H-benzimidazole-2-carboxamide in the form of a crystalline powder (type A crystal, 1195 g, yield 91.2%).

Reference Example 3. 1- (4-Methoxybutyl) hydrochloride - ^ (2-methylpropyl) - ^ [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole-2 -carboxamide (type A crystal).

1- (4-Methoxybutyl) hydrochloride ^ - (2-methylpropyl) - ^ [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole-2-carboxamide (crystal type A, 190 g) are suspended in a mixture of 2 propanol ethyl acetate (1: 7.5, 2153 ml). Then the mixture is transferred into the solution by heating to 40-50 ° C. After confirming the dissolution, heptane (1330 ml) is added dropwise. Then seed crystals (190 mg) of type A crystal are added, obtained according to the method described in Example 265 in GSO 2009/154300, and heptane (570 ml) is added dropwise. After stirring, the mixture is cooled to 25-30 ° C and stirred for 1 hour. After stirring, the mixture is heated to 40-50 ° C and stirred for 1 hour. After stirring, the mixture is cooled to 20-25 ° C and stirred at the same temperature. for 1 h. After stirring, the crystals were collected by filtration and washed with ethyl acetate-heptane (1: 1, 570 ml), and wet crystals were obtained. The obtained wet crystals are dried under reduced pressure at 50 ° C. and a crystalline powder is obtained having a powder X-ray diffraction pattern showing characteristic peaks showing crystal lattice parameters (b) of about 17.18,

- 10 022094

12.27, 8.73, 7.13, 4.76 angstroms (type A crystal, 155.7 g, 81.9% yield). X-ray powder diffraction results are shown in the following table.

Table 1. The results of powder x-ray (crystal type A)

2Θ (°) The value of ά (A) Relative intensity (%) 5.14 17.18 one hundred 7.20 12.27 25 10.12 8.73 43 12.40 7.13 59 18.64 4.76 one hundred

As a result of the analysis for the content of hydrochloric acid, it is ascertained that the above hydrochloride is monohydrochloride.

The theoretical content of hydrochloric acid is 6.8%, the measured value of 6.8%.

Reference Example 4. tert-Butyl- (38.5P) -3 - [{[1- (4-methoxybutyl) -1H-benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin- 4-ylcarbonyl) piperidine-1-carboxylate.

1) Add toluene (500 ml) to o-nitroaniline (50.0 g, 0.362 mol), tetrabutylammonium bromide (58.3 g, 0.181 mol) and potassium bromide (43.1 g, 0.362 mol). At 20-30 ° C, 1-chloro-4-methoxybutane (66.6 g, 0.543 mol) and a 50% (w / v) aqueous sodium hydroxide solution (145 ml, 1.81 mol) are added. The reaction mixture is heated at 85-95 ° C and stirred for 6 hours. After cooling to 20-30 ° C, the reaction mixture is washed successively with water (250 ml), 1Ν hydrochloric acid (250 ml x 2), 5% (wt. ./ob.) an aqueous solution of sodium bicarbonate (250 ml) and water (250 ml). The organic layer was concentrated under reduced pressure to a volume of 250 ml, toluene (100 ml) was added and a toluene solution (350 ml) of W (4-methoxybutyl) -2-nitroaniline was obtained (yield 100%).

Я-NMR (300 MHz, SBS1 ₃ ) δ 1.64-1.89 (m, 4H), 3.25-3.39 (m, 2H), 3.35 (s, 3H), 3.44 ( t, 1 = 6.1 Hz, 2H), 6.63 (ddd, 1 = 8.5, 6.9, 1.2 Hz, 1H), 6.86 (dd, 1 = 8.5, 1, 2 Hz, 1H), 7.43 (ddd, 1 = 8.5, 6.9, 1.5 Hz, 1H), 8.07 (br s, 1H), 8.17 (dd, 1 = 8 5, 1.5 Hz, 1H).

2) To a toluene solution (350 ml) of F (4-methoxybutyl) -2-nitroaniline was added 10% Ρά / C (Ktipa, 50% aqueous product, 10.0 g) and toluene (100 ml). The mixture is stirred at 20-30 ° C for 3 hours in a hydrogen atmosphere (0.1 MPa). The catalyst was filtered off under nitrogen and the residue washed with toluene (100 ml). Water was removed from the filtrate by separation, magnesium sulfate was added at 2030 ° C, and the mixture was stirred at the same temperature for 30 minutes. Magnesium sulfate was filtered off, the residue was washed with toluene (100 ml) to obtain a toluene solution of G (4-methoxybutyl) -phenylenediamine (yield 100%).

Я-NMR (300 MHz, SBS1 ₃ ) δ 1.67-1.78 (m, 4H), 3.12-3.14 (m, 2H), 3.32 (broad, 3H), 3.35 ( s, 3H), 3.413.47 (m, 2H), 6.63-6.69 (m, 2H), 6.69-6.74 (m, 1H), 6.82 (td, 1 = 7, 57, 1.58 Hz, 1H).

3) A solution of G (4-methoxybutyl) -o-phenylenediamine in toluene is cooled to 0-10 ° C and acetic acid (65.2 g, 1.09 mol) and methyl-2,2,2-trichloroacetimidate are added (70, 3 g, 0.398 mol). After stirring at 0-10 ° C for 30 minutes, the mixture was stirred at 20-30 ° C for 3 hours. The reaction mixture was washed successively with 5% (w / v) brine (250 ml), a mixed solution of 2Ν chloride hydrogen acid / 5% (w / v) salt solution (1: 1, 250 ml x 2), 5% (w / v) aqueous sodium bicarbonate (250 ml) and 5% (w / v) .) salt solution (250 ml). In a stream of nitrogen, magnesium sulfate is added to the organic layer at 20-30 ° C and the mixture is stirred at the same temperature for 30 minutes. Magnesium sulfate is filtered off and the residue washed with toluene (100 ml). The filtrate was concentrated under reduced pressure to obtain a residue of 150 ml. The concentrated solution was stirred at 20-30 ° C., crystals precipitated and heptane (750 ml) was added dropwise. The crystal solution is heated at 40-50 ° C and stirred for 30 minutes. After stirring, the solution is cooled to 0-10 ° C and stirred at this temperature for 2 hours. The precipitated crystals are collected by filtration, washed with toluene-heptane (1: 5, 150 ml), dried under reduced pressure at 40 ° C and 1- (4-methoxybutyl) -2-trichloromethyl-1H-benzimidazole is obtained as pale brown crystals (96.5 g, 82.9% yield relative to o-nitroaniline).

Ή-ΗΜΡ (300 MHz, SBS1 ₃ ) δ 1.68-1.85 (m, 2H), 1.99-2.17 (m, 2H), 3.37 (s, 3H), 3.48 ( t, 1 = 6.1 Hz, 2H), 4.50-4.65 (m, 2H), 7.27-7.49 (m, 4H), 7.82-7.93 (m, 1H) .

Elem. analysis. Calculated for 0 ₃ Η ₁₅ Ο ₃ Ν ₂ Θ: C 48.55; H 4.70; N, 8.71; C1 33.07. Found: C, 48.30; H 4.61; N, 8.74; C1 33.30.

4) To a mixture of pyridine-3,5-dicarboxylic acid (110 g, 0.66 mol) and methanol (660 ml) at 50 ° C. or lower temperature, conc. sulfuric acid (226.0 g, 2.30 mol). After that, the mixture is heated at 55-65 ° C and stirred for 7 hours. The reaction mixture is cooled to 40-50 ° C and water (220 ml) is added. In addition, at 40-50 ° C. a 5% aqueous solution of ammonia (about 1.10 L) is added dropwise in order to bring the pH of the mixture to 8.0-8.5. After stirring at 40-50 ° С for 11 minutes, the mixture was cooled to 0-10 ° С and stirred for 1 h. The precipitated crystals were collected by filtration, washed successively with methanol-water (1: 3, 165 ml) and water (440 ml), dried under reduced pressure at 50 ° C and get dimethylpyridin-3,5-dicarbonate in the form of white crystals (105.0 g, yield 82.0%).

Ή-NMR (300 MHz, COC1 ₃ ) δ 4.00 (s, 6H), 8.87 (s, 1H), 9.37 (s, 2H).

Elem. analysis. Calculated for C ₉ H ₉ NO ₄ : C 55.39; H 4.65; N, 7.18; About 32.79. Found: C 55.42; H 4.65; N

7.16.

5) Dimethylpyridin-3,5-dicarbonate (100 g, 0.51 mol) and dimethylacetamide (400 ml) were charged into an autoclave (1 L), trifluoroacetic acid (59.2 ml) was added dropwise at 30 ° C or lower temperature. 0.77 mol) and 10% Pb-C (PE-type, 20.0 g) are added. The mixture is stirred at 55-65 ° C for 12 hours in a hydrogen atmosphere (0.5-0.7 MPa). The catalyst is filtered off and the residue washed with dimethylacetamide (50 ml x 2). The filtrates are combined and triethylamine (77.8 g, 0.77 mol) is added dropwise at 20-30 ° C. to adjust the pH of the mixture to 9.0-10.0. At 30-40 ° C, di-tert-butyl dicarbonate (134 g, 0.614 mol) was added dropwise and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was cooled to 20-30 ° C, ethyl acetate (600 ml) was added and the mixture washed with water (900 ml). The aqueous layer was again extracted with ethyl acetate (400 ml). The organic layers are combined and washed successively with 5% (w / v) citric acid - 10% (w / v) brine (600 ml), 3% aqueous sodium bicarbonate (600 ml) and water (600 ml) . The organic layer was concentrated under reduced pressure to a volume of 200 ml, methanol (250 ml) was added to the concentrated solution, and the mixture was concentrated under reduced pressure to a volume of 200 ml. Methanol (250 ml) was again added to the concentrated solution, the mixture was concentrated under reduced pressure to a volume of 200 ml, and methanol (2.40 L) was added. Water (18.5 g, 1.03 mol) and cesium carbonate (417 g, 1.28 mol) were added to the resulting solution, and the mixture was stirred at 55-65 ° C. for about 24 hours. The reaction mixture was cooled to 20-30 ° C and concentrated to a volume of 700 ml and tetrahydrofuran (500 ml) was added. To the resulting solution at 15-35 ° C was added dropwise 2Ν hydrochloric acid (1.28 L, 2.56 mol), the mixture was adjusted to pH 3.0-3.5 and stirred at 20-30 ° C for 30 min. The mixture was extracted with ethyl acetate (750 ml x 2) and the organic layer was washed with 10% (w / v) brine (500 ml x 3). The organic layer was concentrated under reduced pressure to a volume of 300 ml, and ethyl acetate was added to a volume of 650 ml. The concentrate is heated to 55-65 ° C. and heptane (500 ml) is added dropwise. The mixture was cooled to 20-30 ° C and stirred for 1 h. The precipitated crystals were collected by filtration, washed with ethyl acetate-heptane (1: 1, 120 ml), dried under reduced pressure at 50 ° C, and 1- (tert β-butoxycarbonyl) piperidine-3,5-dicarboxylic acid as a white crystalline powder (113.3 g, yield 80.9%).

Ή-NMR (300 MHz, DMSO- ₆ ) δ 1.40 (s, 9H), 1.44-1.61 (m, 1H), 2.21-2.26 (m, 1H), 2, 31-2.41 (m, 2H); 4.10-4.12 (m, 2H).

Elem. analysis. Calculated for ν ₂ Ηι ₉ ΝΟ ₆ : C 52.74; H 7.01; N, 5.13; About 35.13. Found: C, 52.96; H 6.99; N, 5.39.

6) In a stream of nitrogen, 1- (tert-butoxycarbonyl) piperidine-3,5-dicarboxylic acid (5.00 g, 18.3 mmol) is suspended in tetrahydrofuran (10.0 ml), and added at 20-30 ° C. dropwise trifluoroacetic anhydride (3.80 g, 27.5 mmol). Upon completion of the dropwise addition, the mixture was stirred at 20-30 ° C. for 1 hour. Heptane (20.0 ml) was added dropwise to the reaction mixture at 20-30 ° C. and the mixture was cooled to 0-10 ° C. and stirred for 3 hours. The precipitated crystals were collected by filtration, washed with heptane (3.00 ml), dried under reduced pressure at 40 ° C to obtain tert-butyl-2,4-dioxo-3-oxa-7azabicyclo [3.3.1] nonane -7-carboxylate in the form of a white crystalline powder (4.03 g, yield 86.1%).

Я-NMR (300 MHz, ATP1 ₃ ) δ 1.43 (s, 9H), 1.93-1.99 (m, 1H), 2.40-2.46 (m, 1H), 3.06- 3.11 (m, 4H); 4.504.54 (m, 2H).

Elem. analysis. Calculated for SCN ^ Ol C 56.46; H 6.71; N, 5.49; About 31.34. Found: C 56.51; H, 6.63; N, 5.69.

7) Guanidine (69.9 g, 0.215 mol) and tetrahydrofuran (200 ml) are charged in a stream of nitrogen, and the mixture is cooled to -5 - 5 ° C. At the same temperature, tert-butyl-2,4-dioxo-3-oxa-7-azabicyclo [3.3.1] nonane-7-carboxylate (50.0 g, 0.196 mol) was added and the used container was washed with tetrahydrofuran (50 , 0 ml). At -5 - 5 ° C, methanol (9.41 g, 0.294 mol) was added dropwise and the mixture was stirred at -5 5 ° C for 2 hours. Ethyl acetate (350 ml) and 20% (w / w) were added to the reaction mixture. vol.) an aqueous solution of citric acid (250 ml) and the mixture is separated. The aqueous layer was again extracted with ethyl acetate (125 ml x 2). The organic layers are combined and washed successively with 20% (w / v) aqueous citric acid solution (250 ml) and water (250 ml x 2). The organic layer was concentrated under reduced pressure. Ethanol (100 ml) and ethyl acetate (450 ml) were added to the residue, the mixture was heated to 60-70 ° C and (P) -phenethylamine (23.7 g, 0.196 mol) was added. The mixture was stirred at 50-60 ° C for 1 h, at 20-30 ° C for 1 h and at -5 - 5 ° C for 1 h. The precipitated crystals were collected by filtration, washed with ethanol-ethyl acetate (2 : 9, 100 ml), dried under reduced pressure at 50 ° C and get

- 12 022094 salt of (1K) -1-phenylethylamine (38.5K) -1- (tert-butoxycarbonyl) -5- (methoxycarbonyl) iiieridine-3carboxylic acid as a white crystalline powder (55.7 g, 69.6% yield )

Я-NMR (300 MHz, DMSO-b ₆ ) δ 1.42 (s, 9H), 1.43-1.51 (m, 3H), 2.06-2.14 (m, 1H), 2, 21-2.26 (m, 1H), 2.39-2.44 (m, 1H), 2.52-2.53 (m, 1H), 2.57 (br s, 2H), 3, 64 (s, 3H), 4.12 (br s, 2H), 4.19-4.26 (m, 1H), 7.30-7.40 (m, 3H), 7.45-7, 48 (m, 2H).

Elem. analysis. Calculated for C ₂ 1H ₃₂ N ₂ O ₆ : C 61.75; H, 7.90; N, 6.86; About 23.50. Found: C, 61.54; H 7.77; N, 6.86.

8) Download the salt of (1K) -1-phenylethylamine (38.5K) -1- (tert-butoxycarbonyl) -5- (methoxycarbonyl) iiieridine-3-carboxylic acid (20.0 g, 49.0 mmol), methanol ( 20 ml) and water (80 ml). At 20-30 ° C, a solution of citric acid (11.3 g, 58.8 mmol) in water (20.0 ml) was added to the koil, and the mixture was stirred for 5 hours with the same temperature. The crystals that precipitated out collected by filtration, triturated with water (60 ml) and dried under a reduced pressure of 50 ° C, and (38.5K) -1- (tert-butoxycarbonyl) -5- (methoxycarbonyl) iieridine-3-carboxylic acid is obtained in the form of a white crystalline powder ( 13.5 g, yield 96.1%).

Я-NMR (300 MHz, SES1 ₃ ) δ 1.40 (s, 9H), 1.46-1.59 (m, 1H), 2.22-2.27 (m, 1H), 2.37- 2.45 (m, 2H), 2.632.73 (m, 2H), 3.63 (s, 3H), 4.14 (br s, 2H), 12.51 (br s, 1H).

Elem. analysis. Calculated for ScN ₂ ^ O ₆ : C 54.35; H 7.37; N, 4.88; About 33.41. Found: C 54.14; H 7.28; N, 4.85.

9) In a stream of nitrogen load (38.5K) -1- (tert-butoxycarbonyl) -5- (methoxycarbonyl) iiieridine-3carboxylic acid (30.0 g, 104 mmol), triethylamine (31.7 g, 313 mmol) and toluene (180 ml). At 15-35 ° C, a solution of diphenylphosphoryl azide (28.7 g, 313 mmol) in toluene (30.0 ml) is added dropwise. After stirring the iris at 30 ± 5 ° C for 30 minutes, the mixture is heated to 65-75 ° C and stirred for 30 minutes. At 60-70 ° C, benzyl syirt (12.4 g, 115 mmol) was added to the koil. The mixture was heated to 8090 ° C and stirred for 3 hours. The reaction mixture was cooled to 20-30 ° C, a solution of sodium nitrite (7.20 g, 104 mmol) in water (150 ml) was added, and the mixture was stirred for 1 hour. and the aqueous layer is separated. The organic layer is washed successively with a 5% (w / v) aqueous solution of sodium bicarbonate (150 ml), a 20% (w / v) aqueous solution of citric acid (150 ml) and a 5% (w / v) solution salt (150 ml), and the organic layer was concentrated under reduced pressure. Methanol (60.0 ml) was added to the residue, and the mixture was concentrated under reduced pressure. A similar operation is performed again. Methanol was added to the residue to give a mixture (90.0 g). At 15-35 ° C, a 2N aqueous solution of sodium hydroxide (62.6 ml, 125 mmol) was added and the mixture was stirred at 30 ± 5 ° C for 1 h. At 20-30 ° C, methanol (120 ml) and 20% were added. (wt./about.) an aqueous solution of citric acid (300 ml) to bring the pH of the mixture to 3.0-3.5. After stirring at 50-60 ° C for 30 minutes, the mixture was cooled to 20-30 ° C and stirred for 1 hour. In addition, the mixture was stirred at 0-10 ° C for 1 hour. The precipitated crystals were collected by filtration, washed with water (90.0 ml) and dried under reduced pressure of iri 50 ° C, and get (3K, 58) -5 - {[(benzyloxy) carbonyl] amino} -1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid in the form of a white crystalline powder (35.0 g, 88.6% yield).

Я-NMR (300 MHz, DMSO-b ₆ ) δ 1.41 (s, 9H), 2.11 (d, 1 = 12.4 Hz, 1H), 2.40-2.48 (m, 4H) 2.62 (br s, 1H), 4.08 (t, 1 = 14.4 Hz, 2H), 5.04 (s, 2H), 7.31-7.41 (m, 5H), 12.53 (br s, 1H).

Elem. analysis. Calculated for C19H _{2 &} L ₂ O ₆ : C, 60.30; H, 6.93; N, 7.40; About 25.37. Found: C, 60.03; H 6.99; N, 7.41.

10) In a stream of nitrogen load (3K, 58) -5 - {[(benzyloxy) carbonyl] amino} -1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (30.0 g, 79.3 mmol), morpholine (7.60 g, 87.2 mmol), 1-hydroxybenzotriazole monohydrate (2.43 g, 15.9 mmol) and dimethylacetamide (90.0 ml). At 20-30 ° C, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (16.7 g, 87.1 mmol) was added and the mixture was stirred at 45-55 ° C for 1 h. At 45-55 ° Tetrahydrofuran (90.0 ml) and water (210 ml) are successively added dropwise and the mixture is stirred for 1 h. The mixture is cooled to 20-30 ° C and stirred for 1 h, the precipitated crystals are collected by filtration, washed with the mixture tetrahydrofuranvoda (1: 3, 120 ml) and dried under reduced pressure at 50 ° C to obtain tert-butylpiperidin-1 (38.5K) -3 - {[(benzyloxy) carbonyl] amino} -5- (morpholine-4- Ilcarbonyl) carboxylate in as a white crystalline powder (32.7 g, yield 92.3%).

Ή-ΗΜΡ (300 MHz, DMSO-b ₆ ) δ 1.41 (s, 9H), 1.49-1.57 (m, 1H), 1.87 (d, 1 = 12.3 Hz, 1H) 2.43 (br s, 1H), 2.63-2.71 (m, 1H), 2.79-2.83 (m, 1H), 3.37-3.54 (m, 9H) 3.89 (d, 1 = 11.5 Hz, 1H); 4.06 (br s, 1H); 5.03 (s, 2H); 7.30-7.38 (m, 5H).

Elem. analysis. Calculated for C ₂₃ H ₃₃ ^ O ₆ : C 61.73; H 7.43; N, 9.39; About 21.45. Found: C, 61.59; H 7.50; N, 9.43.

11) Download tert-butyl ieridine-1- (38.5K) -3 - {[(benzyloxy) carbonyl] amino} -5- (morpholine-4ylcarbonyl) carboxylate (30.0 g, 67.0 mmol), isobutylaldehyde (7 25 g, 101 mmol), 10% S-C (PE type, 1.50 g) and methanol (240 ml). The mixture is stirred at 20-30 ° C for 4 hours in a hydrogen atmosphere (0.2-0.3 MPa). The catalyst was filtered off and the residue washed with methanol (60.0 ml). The filtrate was concentrated under reduced pressure, ethyl acetate (60.0 ml) was added and the mixture was again concentrated under reduced pressure. Ethyl acetate was added to the residue to a volume of 360 ml. The mixture was heated to 45-55 ° C and succinic acid (7.90 g, 67.0 mmol) was added. The mixture was stirred at 45-55 ° C for 1 h, cooled to 20-30 ° C and stirred for 1 h. The precipitated crystals were collected by filtration, washed with ethyl acetate (90.0 ml) and dried under reduced pressure at 50 ° C and get succinate tert-butyl- (3§, 5K) -3 - [(2-methylpropyl) amino] -5- (morpholin-4-ylcarbonyl) piperidine-1-carboxylate in the form of a white crystalline powder (30.2 g yield 92.5%).

¹ H-NMR (300 MHz, Ό ₂ Θ) δ 1.02 (s, 3H), 1.04 (s, 3H), 1.47 (s, 9H), 1.97-2.09 (m, 2H), 2.26-2.30 (m, 1H), 2.55 (s, 4H), 2.99 (d, 1 = 7.0 Hz, 2 N), 3.23 (broad s, 1H), 3.39-3.45 (m, 2H), 3.53-3.80 (m, 10H), 3.82-3.93 (br s, 1H).

Elem. analysis. Calculated for C ₂ zN ₄₁ N ₃ O ₈ : C 56.66; H 8.48; N, 8.62; About 26.25. Found: C 56.48; H 8.46; N, 8.39.

12) Download tert-butyl- (3§, 5K) -3 - [(2-methylpropyl) amino] -5- (morpholin-4-ylcarbonyl) piperidine-1-carboxylate succinate (30.3 g, 62.2 mmol ), acetonitrile (60.0 ml) and water (40.0 ml). Potassium carbonate (34.4 g, 0.249 mmol) is then added and the mixture is stirred for 10 minutes. 1- (4methoxybutyl) -2-trichloromethyl-1H-benzimidazole (20.0 g, 62.2 mmol) was added and the mixture was stirred at 7080 ° C. for 2 hours. Dimethyl sulfoxide (15.0 ml) was added and the mixture was stirred at 70 -80 ° C for 6 hours. The reaction mixture was cooled to 20-30 ° C, water (120 ml) and toluene (240 ml) were added, and the mixture was separated. The organic layer is washed successively with 10% (w / v) brine (100 ml), 10% (w / v) aqueous citric acid (100 ml) and 10% (w / v) brine ( 100 ml). To the organic layer, activated charcoal §La8ad1A (1.0 g) was added and the mixture was stirred at 2030 ° C for 30 minutes. Activated carbon is filtered off and washed with toluene (40.0 ml) and the filtrate is concentrated under reduced pressure to 110 ml. After heating to 35-45 ° C, heptane (280 ml) is added dropwise. At 35-45 ° C, tert-butyl- (3§, 5K) -3 - [{[1- (4-methoxybutyl) -1Nbenzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- ( morpholin-4-ylcarbonyl) piperidine-1-carboxylate in the form of crystals (10 mg) and the mixture was stirred at the same temperature for 1 hour. At 3545 ° C, heptane (140 ml) was added dropwise and the mixture was stirred for 30 minutes. The mixture was cooled to 20-30 ° C and stirred for 2 hours. The precipitated crystals were collected by filtration, washed with toluene-heptane (1: 5, 40.0 ml), dried under reduced pressure at 50 ° C, and tert-butyl- (3§, 5K) -3 - [{[1- (4-methoxybutyl) -1H-benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5 (morpholin-4-ylcarbonyl) piperidin-1- carboxylate in the form of a pale yellowish-white crystalline powder (27.7 g, yield 74.2%).

'H-NMR (300 MHz, SES1 ₃ ) δ 0.68-0.80 (m, 3H), 0.96-1.08 (m, 3H), 1.31 (broad s, 5H), 1 49 (s, 4H), 1.611.71 (m, 2H), 1.71 (broad s, 0.5H), 1.92-2.05 (m, 3H), 2.05-2.24 (m, 2H), 2.45 (broad s, 1H), 2.60 (broad s, 1H), 2.72-2.96 (m, 2H), 3.26-3.35 (m , 3H), 3.35-3.47 (m, 2H), 3.47-3.73 (m, 10H), 4.02-4.26 (m, 2H), 4.26-4.34 (m, 1H), 4.34-4.47 (m, 0.5H), 7.25-7.29 (m, 1H), 7.29-7.41 (m, 1H), 7.41 -7.53 (m, 1H), 7.64 (br s, 0.5H), 7.79 (d, 1 = 8.2 Hz, 0.5H).

Elem. analysis. Calculated for C ₃₂ H ₄₉ ^ O ₆ : C 64.08; H, 8.23; N, 11.68; About 16.01. Found: C, 63.82; H, 8.12; N, 11.64.

Example 1. Hydrochloride of 1- (4-methoxybutyl) -H- (2-methylpropyl) -P - [(3§, 5K) -5- (morpholine-4ylcarbonyl) piperidin-3-yl] -1H-benzimidazole-2- carboxamide (type B crystal).

tert-Butyl- (3§, 5K) -3 - [{[1- (4-methoxybutyl) -1H-benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4-ylcarbonyl ) piperidine-1-carboxylate (20 kg) is added to the previously prepared 3 N hydrochloric acid (20 l of concentrated hydrochloric acid, water up to 60 l), and then ethyl acetate (4 l) is added. Upon completion of the addition, the mixture is stirred at 15-25 ° C for 3 hours or more. Upon completion of the reaction, water (100 L) and ethyl acetate (200 L) are added at the same temperature. Upon completion of the addition at 25 ° C. or lower, the mixture was adjusted to a pH of about 725% aqueous ammonia (about 19 L). After adjusting the pH, the extracted organic layer was retained, and the aqueous layer was again extracted with ethyl acetate (200 L). The newly extracted organic layer was retained and the aqueous layer was again extracted with ethyl acetate (200 L). The same operation is repeated again, the resulting organic layers are combined and the mixture is concentrated.

After concentration, ethyl acetate (100 L) was added and the mixture was concentrated again. The same operation is repeated again. After concentration, ethyl acetate (125 L) and 2-propanol (20 L) were added and the mixture was heated to 35-45 ° C. When the temperature rises, a 4N solution of hydrogen chloride in ethyl acetate (8.34 L) is added at this temperature. Upon completion of the addition, seed crystals (20 g) of a type B crystal obtained according to the method described in Example (6-3) are added at the same temperature, and the mixture is stirred for 30 minutes or more. After stirring at 35-45 ° C, heptane (200 L) is added dropwise over 30 minutes or more. Upon completion of the dropping, the mixture is stirred at the same temperature for 30 minutes or more. Then the mixture is gradually cooled.

- 14 022094 to 20-30 ° C and stirred at this temperature for 30 minutes or more. After stirring, the crystals were collected by filtration, washed with a mixture of 2-propanol-ethyl acetate-heptane (1: 6: 8, 60 L) and wet crystals were obtained. The obtained wet crystals are dried under reduced pressure at 4555 ° C. to obtain 1- (4-methoxybutyl) -P- (2-methylpropyl) -L - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidine hydrochloride -3-yl] -1H-benzimidazole-2-carboxamide in the form of a crystalline powder (type B crystal, 16.446 kg, yield 92.0%).

Example 2. Hydrochloride of 1- (4-methoxybutyl) -M- (2-methylpropyl) -L - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole- 2-carboxamide (type B crystal).

1- (4-Methoxybutyl) -P- (2-methylpropyl) -L - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole-2-carboxamide hydrochloride (Type B crystal, 16.3 kg) are suspended in 2-propanol (65.2 L). Then the suspension is dissolved by heating it to 65-75 ° C. After confirming the dissolution, perform filtration to remove the powder and the residue washed with 2-propanol (16.3 l). The obtained filtrate and the washing liquid are cooled to 50-60 ° C and seed crystals (16.3 g) of a type B crystal obtained according to the method described in example (6-3) are added. After addition, the mixture is cooled to 45-55 ° C, and the mixture is stirred at this temperature for 30 minutes or more. After stirring at the same temperature, heptane (326 L) is added dropwise over 30 minutes or more. Upon completion of the dropping, the mixture is stirred at the same temperature for 1 hour or more. After stirring, the mixture is cooled to 20-30 ° C and stirred at this temperature for 1 h or more. After stirring, the crystals were collected by filtration and washed with a mixture of 2-propanol-heptane (1: 4, 48.9 L), and wet crystals were obtained. The obtained wet crystals are dried under reduced pressure at 45-55 ° C. and a crystalline powder is obtained (type B crystal, 13.28 kg, 81.5% yield). Melting point 198 ° C.

As a result of the analysis for the content of hydrochloric acid, it is ascertained that the above hydrochloride is monohydrochloride.

The theoretical content of hydrochloric acid is 6.8%, the measured value of 6.9%.

Example 3. Hydrochloride 1- (4-methoxybutyl) -M- (2-methylpropyl) -L - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole- 2-carboxamide (type B crystal).

Type A crystals (3.0 g) obtained according to the method described in Reference Example 1 were suspended in 2-propanol (30 ml) at room temperature and the suspension was dissolved at 30-40 ° C. After confirming the dissolution, add seed crystals (0.003 g) of the type B crystal obtained according to the method described in example 4. After the addition is complete, the mixture is cooled to 20-30 ° C and stirred overnight. After stirring, the crystals were collected by filtration and washed with 2 propanol (9 ml) to obtain wet crystals. The obtained wet crystals were dried under reduced pressure at 50 ° C. and a crystalline powder was obtained (type B crystal, 2.03 g, yield 67.7%).

Example 4. Hydrochloride of 1- (4-methoxybutyl) -L- (2-methylpropyl) -P - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole- 2-carboxamide (type B crystal).

Type A crystals (550 g) obtained according to the method described in Reference Example 2 were suspended in methyl ethyl ketone (4400 ml) and the suspension was heated to 45-55 ° C. After stirring, methyl ethyl ketone (1000 ml) was added. Upon completion of the addition, the mixture is stirred, while the temperature is raised to 50-60 ° C, cooled to 20-30 ° C and stirred. After stirring, the crystals were collected by filtration and washed with methyl ethyl ketone (80 ml) to obtain wet crystals. The obtained wet crystals are dried under reduced pressure at 45-50 ° C. and a crystalline powder is obtained (type B crystal, 531.95 g, yield 96.7%).

Example 5. 1- (4-Methoxybutyl) -M- (2-methylpropyl) -L - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole- hydrochloride 2-carboxamide (type B crystal).

Type A crystals (6.0 g) obtained according to the method described in Reference Example 2 were suspended in a mixture of 2-propanol ethyl acetate (1:15, 54 ml) at room temperature and the suspension was stirred while heating to 45-55 ° C. When dissolution occurs, precipitation of crystals is observed. After precipitation of crystals was noted, the mixture was cooled to 2030 ° C and stirred overnight. After stirring, the crystals were collected by filtration and washed with ethyl acetate (18 ml) to obtain wet crystals. The obtained wet crystals were dried under reduced pressure at 50 ° C. and a crystalline powder was obtained (type B crystal, 5.72 g, yield 95.3%).

Example 6. Hydrochloride 1- (4-methoxybutyl) -M- (2-methylpropyl) -L - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole- 2-carboxamide (type B crystal).

(6-1) 1- (4-Methoxybutyl) -M- (2-methylpropyl) -L - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H- hydrochloride benzimidazole-2-carboxamide (type B crystal, 45.0 g) was suspended in 2-propanol (360 ml). Then the suspension is dissolved by heating to 55-60 ° C. After confirming the dissolution, perform filtration to remove the powder and the residue washed with 2-propanol (45 ml). Filtrate and rinse

- 15 022094 liquid after filtration to remove the powder is stirred at 55-65 ° C, but the precipitation is not convinced. After verifying this, the solution is cooled to 35-45 ° C. After cooling, seed crystals (0.045 g) of type B crystals, obtained according to the method described in Example 3, are added. Upon completion of the addition, the mixture is stirred at the same temperature for 1 hour or more. After stirring at the same temperature, heptane (1620 ml) was added dropwise. Upon completion of the dropping, the mixture is stirred at the same temperature for 30 minutes or more. After stirring, the mixture is cooled to 20-30 ° C and stirred for 1 h or more. After stirring, the crystals were collected by filtration and washed with a mixture of 2-propanol-heptane (1: 4, 135 ml), and wet crystals were obtained. The obtained wet crystals are dried under reduced pressure at 50 ° C. and 1- (4-methoxybutyl) -Y- (2-methylpropyl) -M - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidine hydrochloride is obtained -yl] -1H-benzimidazole-2-carboxamide in the form of a crystalline powder (type B crystal, 40.37 g, yield 89.7%).

(6-2) 1- (4-Methoxybutyl) -M- (2-methylpropyl) -H - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H- hydrochloride benzimidazole-2-carboxamide (type B crystal, 500 g) was suspended in 2-propanol (4000 ml). Then the suspension is dissolved by heating to 55-65 ° C. After confirming the dissolution, perform filtration to remove the powder, and the residue is washed with 2-propanol (250 ml). Similarly, 1- (4-methoxybutyl) -H- (2-methylpropyl) -M - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin3-yl] -1H-benzimidazole-2-carboxamide hydrochloride (type B crystal, 500 g) are suspended in 2-propanol (4000 ml). Then the suspension is dissolved by heating to 55-65 ° C. After confirming the dissolution, perform filtration to remove the powder and the residue washed with 2-propanol (250 ml). Two filtrates and washings after filtration to remove the powder are combined and stirred at 55-65 ° C, but they are not convinced of the precipitation. Used containers were washed with 2-propanol (500 ml). After making sure that there is no precipitation, the solution is cooled to 35-45 ° C. After cooling, seed crystals (1 g) of type B crystals obtained according to the method described in example (6-1) are added, and heptane (36000 ml) is added dropwise. Upon completion of the dropping, the mixture is stirred at the same temperature for 1 hour or more. After stirring, the mixture was cooled to 2030 ° C and stirred for 1 h or more. After stirring, the crystals were collected by filtration and washed with a mixture of 2-propanol-heptane (1: 4, 3000 ml), and wet crystals were obtained. The obtained wet crystals are dried under reduced pressure at 50 ° C. and 1- (4methoxybutyl) -I- (2-methylpropyl) -M - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidine-3 hydrochloride is obtained -yl] -1H-benzimidazole-2-carboxamide in the form of a crystalline powder (type B crystal, 880.53 g, 88.1% yield). The obtained crystals of type B are crushed in Po \ ush MS and get a crystalline product (crushed product, crystal type B, 849 g).

(6-3) Methane sulfonate monohydrate 1- (4-methoxybutyl) -I- (2-methylpropyl) -M - [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H -benzimidazole-2-carboxamide (9000 g) is dissolved in water (45000 ml). The pre-prepared aqueous solution of sodium bicarbonate (2464 g of ΝαНСО ₃ , 45000 ml of water) was added to the solution, and the mixture was stirred. Ethyl acetate (90,000 ml) was added with stirring and the mixture was stirred. After stirring, ethyl acetate (90,000 ml) was added to the extractable aqueous layer and the mixture was stirred. After stirring, ethyl acetate (90,000 ml) was added again to the extracted aqueous layer and the mixture was stirred. The resulting organic layers were combined and concentrated to about 27 L. Ethyl acetate (45000 ml) was added to the concentrated solution, and the mixture was concentrated to about 27 L. The concentrated solution was left to stand overnight. Ethyl acetate (45000 ml) was added to the concentrated solution overnight, and the mixture was concentrated to about 27 L. Ethyl acetate (45000 ml) and 2-propanol (9000 ml) were added to the concentrated solution, and the mixture was heated to 45-55 ° C with stirring, and a 4Ν solution of hydrogen chloride in ethyl acetate (4399 ml) was added dropwise during heating at 40 ° C. Upon completion of the dropping, make sure that the solution is homogeneous, and cool it to 35-45 ° С. After cooling, seed crystals (9 g) of a type B crystal obtained according to the method described in example (62) are added, and heptane (90,000 ml) is added dropwise. Upon completion of the dropping, the mixture is stirred at the same temperature for 1 hour or more. After stirring, the mixture is cooled to 20-30 ° C and stirred at this temperature for 1 h or more. The crystals were collected by filtration and washed with a mixture of 2-propanol-ethyl acetate-heptane (1: 6: 8, 9000 ml), and wet crystals were obtained. The obtained wet crystals are dried under reduced pressure at 50 ° C. to give 1- (4-methoxybutyl) ^ - (2-methylpropyl) - ^ [(3§, 5K) -5- (morpholine-4ylcarbonyl) piperidin-3-yl hydrochloride ] -1H-benzimidazole-2-carboxamide in the form of a crystalline powder (type B crystal, 7271 g, yield 92.5%). The obtained hydrochloride of 1- (4-methoxybutyl) ^ - (2-methylpropyl) [(3§, 5K) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole-2-carboxamide (crystal type B, 3500 g) was suspended in 2-propanol (28000 ml). Then the suspension is dissolved by heating to 55-65 ° C. After confirming the dissolution, filtering is performed to remove the powder, and the residue is washed with 2 propanol (3500 ml). The filtrate and washing liquid after filtration to remove the powder are mixed at 55-65 ° C, but they are not convinced of the precipitation. After confirming this, the solution is cooled

- 16 022094 to 35-45 ° С. After cooling, seed crystals (3.5 g) of type B crystals obtained according to the method described in example (6-2) are added, and heptane (126000 ml) is added dropwise. Upon completion of the dropping, the mixture is stirred at the same temperature for 1 hour or more. After stirring, the mixture is cooled to 20-30 ° C and stirred for 1 h or more. After stirring, the crystals were collected by filtration and washed with a mixture of 2-propanol-heptane (1: 4, 10500 ml) to obtain wet crystals. The resulting wet crystals were dried under reduced pressure at 50 ° C. to give 1- (4-methoxybutyl) -M- (2-methylpropyl) -H - [(3§, 5K) -5 (morpholin-4-ylcarbonyl) piperidine hydrochloride 3-yl] -1H-benzimidazole-2-carboxamide in the form of a crystalline powder (type B crystal, 3089 g, 88.3% yield). The obtained crystals of type B (3074 g) are crushed in Roteeg MS, and a crystalline powder is obtained having a powder X-ray diffraction pattern showing characteristic peaks at interplanar distances (ά) near 26.43, 7.62, 4.32, 3.08, 2, 59 and 2.33 angstroms (ground product, type B crystal, 3066 g, 99.7% yield). X-ray powder diffraction results are shown in the following table.

Table 2. The results of powder x-ray (crystal type B)

20 (°) The value of ά (A) Relative intensity (%) 3.34 26.43 one hundred 11.60 7.62 12 20.54 4.32 29th 28.98 3.08 fifteen 34.54 2.59 14 38.64 2,33 eleven

Experimental example 1. Interconversion in suspension.

A type crystal, a type B crystal, and a mixture (1: 1) of a type A crystal and a type B crystal (20 mg in each case) are measured in bottles, isopropyl alcohol (0.2 ml) is added, and suspensions are obtained containing an excess of in them solids. The bottles are hermetically sealed and shaken on a rotary suspension device at ambient temperature for 1 day with uniform rotation. After this, solids are collected by filtration. As a result of measurements by powder X-ray diffraction, it is ascertained that a type A crystal and a 1: 1 mixture of a type A crystal and a type B crystal turn into a type B crystal in one day. A type B crystal shows no changes. The results are given in table. 3.

From the results of the suspension experiment, it is assumed that a type B crystal is thermodynamically stable at ambient temperature when compared with a type A crystal.

Table 3. The results of the experiment with the suspension at ambient temperature

Solvent number connections (mg) Volume solvent (ml) Crystalline the form Before exp. 1 day later Isopropyl alcohol twenty 0.2 Type A Crystal Type B Crystal Isopropyl alcohol twenty 0.2 Type B Crystal Type B Crystal Isopropyl alcohol twenty 0.2 Mixture (1: 1) type A crystal and crystal type B Type B Crystal

Experimental example 2. Analysis of moisture absorption.

Moisture absorption by a type A crystal and a type B crystal is analyzed automatically using a symmetric gravimetric analyzer UE in a step-isothermal mode (8OL-100 for a type A crystal, δΟΑ-CX for a type B crystal). Samples are exposed to various relative humidity (KH) at 25 ° C. The mass of samples at each relative humidity is recorded after reaching equilibrium (weight change less than 0.02% within 10 minutes). The results are given in table. 4.

Table 4

Type A Crystal Type B Crystal Relative humidity (% LV) Level changes mass (%) Relative humidity (% KH) Level mass changes (%} thirty -0, 1 thirty 0,0 fifty 0,0 fifty 0.5 70 7.6 70 0, 9

- 17 022094

Experimental Example 3. Dissolution Test.

2-butanone, ethyl acetate, toluene, n-heptane and tert-butyl methyl ether (5 ml each) were added to type A crystal and type B crystal (each 50 mg) and solubility was determined using a powder suspension (25 ° C, 2 h). The suspensions are centrifuged, the supernatants are filtered through a filter (pore size 0.22 μm) and the solvent is evaporated from the filtrate in a nitrogen atmosphere. The residue obtained by evaporation is dissolved in a mixed solvent with a 50 mM aqueous solution of ammonium acetate / acetonitrile (1: 1) and evaluated by HPLC. The results are given in table. 5.

From the obtained results, it is assumed that the type B crystal is thermodynamically stable at ambient temperature (25 ° C) when compared with a type A crystal.

Table 5

Solubility (μg / ml) Type A Crystal Type B Crystal 2-butanone > 10,000 1800 Ethyl acetate 7300 280 Toluene > 10,000 4.6 N-heptane 0.8 tert-butyl methyl ether 49 thirteen

Industrial applicability

The crystalline form of the present invention has excellent renning inhibitory activity and is useful for the prophylaxis or treatment of hypertension and organ disorders caused by hypertension and similar disorders.

This application is based on patent application No. 2010-137194 filed in Japan, incorporated herein by reference.

Claims (15)

CLAIM 1. The crystalline form of 1- (4-methoxybutyl) ^ - (2-methylpropyl) ^ - [(3§, 5K) -5 (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H-benzimidazole-2- hydrochloride carboxamide having a powder x-ray, showing characteristic peaks at interplanar distances (b) of about 26.43 ± 0.2, 7.62 ± 0.2 and 4.32 ± 0.2 angstroms. 2. The crystalline form according to claim 1, which has a x-ray powder diffraction pattern showing characteristic peaks at interplanar distances (b) of about 26.43 ± 0.2, 7.62 ± 0.2, 4.32 ± 0.2, 3, 08 ± 0.2, 2.59 ± 0.2, and 2.33 ± 0.2 angstroms. 3. A medication for inhibiting renin, containing the crystalline form according to claim 1 or 2. 4. A medicine for the prevention or treatment of a disease with circulatory disorders, containing the crystalline form according to claim 1 or 2. 5. A medicine for the prevention or treatment of hypertension and / or organ disorders caused by hypertension, containing the crystalline form according to claim 1 or 2. 6. A medicament for the prevention or treatment of kidney disease, containing the crystalline form according to claim 1 or 2. 7. A method for the prevention or treatment of a disease with circulatory disorders in a mammal, comprising administering to said mammal an effective amount of a crystalline form according to claim 1 or 2. 8. A method for the prevention or treatment of hypertension and / or organ disorders caused by hypertension in a mammal, comprising administering to said mammal an effective amount of a crystalline form according to claim 1 or 2. 9. A method for the prevention or treatment of a kidney disease in a mammal, comprising administering to said mammal an effective amount of a crystalline form according to claim 1 or 2. 10. The use of the crystalline form according to claim 1 or 2 to obtain a prophylactic or therapeutic agent against a disease with circulatory disorders. 11. The use of the crystalline form according to claim 1 or 2 for the production of a prophylactic or therapeutic agent against hypertension and / or organ disorders caused by hypertension. 12. The use of the crystalline form according to claim 1 or 2 for the production of a prophylactic or therapeutic agent against kidney disease. 13. The use of the crystalline form according to claim 1 or 2 in the prevention or treatment of a disease with circulatory disorders. 14. The use of the crystalline form according to claim 1 or 2 in the prevention or treatment of hypertension and / or organ disorders caused by hypertension. 15. The use of the crystalline form according to claim 1 or 2 for the prevention or treatment of kidney disease.